This invention relates to methods and compositions for treating painful conditions of the anal region and more particularly for treating anal fissures, thrombosed or inflamed hemorrhoids, for pain associated with ligation of internal hemorrhoids and for chronic anal pain.
Anal fissures can be an extremely painful condition. The primary reason for severe pain is spasm of the anal sphincter. This spasm causes ischemia, which both produces pain and interferes with healing (Sharp, American Journal of Surgery, 1996; Volume 171, pages 512-515; Schouten et al., 1993, Scandinavian Journal of Gastroenterology, Volume 31, Supplement 218, pp. 78-81). Spasm of the anal sphincter also plays a role in the pain of inflammatory conditions of the anal region, such as inflamed or recently thrombosed hemorrhoids (Janicke & Pundt, 1996, Emergency Medicine Clinics of North America, Volume 14, pp. 757-788). See also, Madoff, R D., "Pharmacologic Therapy for Anal Fissure," New England Journal of Medicine January 1998 22:338(4) 217-20.
Effective treatments for anal fissures, whether medical or surgical, involve relaxation of the spastic muscle. These treatments include lateral sphincterotomy, injection of the sphincter with botulinum toxin, and application of nitroglycerin ointment. A recent review by Sharp of treatment for chronic anal fissures recommends beginning with nitroglycerin ointment. If the fissure has not healed in six weeks, botulinum toxin injections are given. That review notes that "considerable educational effort is required to successfully adjust the dose" of nitroglycerin (Sharp, 1996, ibid.). It states that nitroglycerin "will often eliminate the severe pain of fissure-in-ano in 1 day" . Schouten et al. (1993, ibid.) used topical isosorbide dinitrate to treat chronic anal fissures, attaining pain relief" within 10 days". Lund & Scholefield (1997, Lancet, Volume 349, pp. 11-14) reported a randomized controlled trial of 0.2% nitroglycerin ointment for anal fissure. At 2 weeks, pain on defecation, as measured by a visual analogue scale (0=no pain, 100=worst pain ever), averaged 33.5 in the treated group, compared with 48.0 in a group treated with placebo, and 73.0 in the same patients at baseline.
Nitroglycerin also has been reported to diminish the pain of thrombosed external hemorrhoids (Gorfine S R 1995, Diseases of the Colon and Rectum, Volume 38, p. 453).
Despite positive clinical trials, nitroglycerin has not been universally accepted as a treatment for anal fissure. According to an experienced rectal surgeon and a gastroenterologist with a special interest in the colon and rectum in a personal communication, many patients simply do not get adequate pain relief from nitroglycerin, even in concentrations as high as 0.5%. My experience with one patient was that nitroglycerin relieved the pain, but only in a concentration that caused a significant headache. Moreover, the patient's anal pain recurred within two hours. The review cited above points out additional problems, including the full day sometimes needed before pain is relieved, and compliance problems because of headaches and the need for frequent dosage adjustments (Sharp, 1996, ibid.). The problems of inadequate relief, short duration of relief, and intolerance of the drug were also described in a recent prospective study of 19 outpatients with chronic anal fissure (Watson et al., 1996, British Journal of Surgery, Volume 83, pp. 771-775). In this study, of the 15 patients who used nitroglycerin for 6 weeks and returned for a second visit, only 6 were symptom-free.
Lidocaine, a topical anesthetic, has been used as a treatment for another painful rectal condition, ulcerative proctitis (Bjorck et al., 1989, Scandinavian Journal of Gastroenterology, Volume 24, pp. 1061-1072). It has also been recommended to relieve pain sufficiently to permit rectal examination of patients with fissures. However, it is not uncommon for pain relief to be insufficient, so that the physician must resort to anesthesia or intravenous sedation, or wait for improvement with conservative treatment (Janicke & Pundt, 1996, ibid.).
Sucralfate, a polysaccharide originally marketed as a treatment for peptic ulcer disease, has since been used with success for a variety of ulcerative conditions of the skin and of mucosa, including pressure ulcers (bedsores), solitary rectal ulcers (Spiliadis et al., 1989, Gastrointestinal Endoscopy, Volume 35, pp. 131-132), and ulcerative colitis (Riley et al., 1989, Scandinavian Journal of Gastroenterology, Volume 24, pp. 1014-1018). It has not been reported as a treatment for anal fissures. Sucralfate, when applied to a damaged mucosa, forms an adherent film that protects the mucosa and promotes healing (Kochhar et al., 1990; Diseases of the Colon and Rectum, Volume 33, pp. 49-51). In addition, sucralfate lowers local levels of the inflammatory mediator PGE.sub.2 (Zahavi et al., 1989; Diseases of Colon and Rectum, Volume 32, pp. 95-98).